Abstract
Congenital bilateral absence of the vas deferens (CBAVD) is a cause of male sterility mostly resulting from mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. The most common defect is the 5T variant at the branch/acceptor site of intron 8, which induces high levels of exon 9 skipping leading to non-functional protein. However, this 5T variant has incomplete penetrance and variable expressivity, suggesting that some other regulatory factors may modulate the splicing of exon 9. To identify such factors, we report here the genetic analysis of a polymorphic locus, M470V, located in exon 10 of the CFTR gene in 60 patients with CBAVD, compared to a normal control population. The statistical analysis showed strong linkage disequilibrium between the 5T allele and the V allele of the M470V polymorphism in the CBAVD population, but not in the normal population. The V allele in a gene carrying 5T could, however, contribute to lowering the level of normal transcripts, as already suggested by in vitro transcriptional studies. These genetic findings, together with previous studies, suggest involvement of the M470V variant in the modulation of the splicing of exon 9 of the CFTR gene.
Full text
PDF
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Chehab F. F., Johnson J., Louie E., Goossens M., Kawasaki E., Erlich H. A dimorphic 4-bp repeat in the cystic fibrosis gene is in absolute linkage disequilibrium with the delta F508 mutation: implications for prenatal diagnosis and mutation origin. Am J Hum Genet. 1991 Feb;48(2):223–226. [PMC free article] [PubMed] [Google Scholar]
- Chillón M., Casals T., Mercier B., Bassas L., Lissens W., Silber S., Romey M. C., Ruiz-Romero J., Verlingue C., Claustres M. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med. 1995 Jun 1;332(22):1475–1480. doi: 10.1056/NEJM199506013322204. [DOI] [PubMed] [Google Scholar]
- Chu C. S., Trapnell B. C., Curristin S., Cutting G. R., Crystal R. G. Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA. Nat Genet. 1993 Feb;3(2):151–156. doi: 10.1038/ng0293-151. [DOI] [PubMed] [Google Scholar]
- Jarvi K., Zielenski J., Wilschanski M., Durie P., Buckspan M., Tullis E., Markiewicz D., Tsui L. C. Cystic fibrosis transmembrane conductance regulator and obstructive azoospermia. Lancet. 1995 Jun 17;345(8964):1578–1578. doi: 10.1016/s0140-6736(95)91131-6. [DOI] [PubMed] [Google Scholar]
- Kerem B., Kerem E. The molecular basis for disease variability in cystic fibrosis. Eur J Hum Genet. 1996;4(2):65–73. doi: 10.1159/000472174. [DOI] [PubMed] [Google Scholar]
- Kerem B., Rommens J. M., Buchanan J. A., Markiewicz D., Cox T. K., Chakravarti A., Buchwald M., Tsui L. C. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989 Sep 8;245(4922):1073–1080. doi: 10.1126/science.2570460. [DOI] [PubMed] [Google Scholar]
- Rave-Harel N., Kerem E., Nissim-Rafinia M., Madjar I., Goshen R., Augarten A., Rahat A., Hurwitz A., Darvasi A., Kerem B. The molecular basis of partial penetrance of splicing mutations in cystic fibrosis. Am J Hum Genet. 1997 Jan;60(1):87–94. [PMC free article] [PubMed] [Google Scholar]
- Riordan J. R., Rommens J. M., Kerem B., Alon N., Rozmahel R., Grzelczak Z., Zielenski J., Lok S., Plavsic N., Chou J. L. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989 Sep 8;245(4922):1066–1073. doi: 10.1126/science.2475911. [DOI] [PubMed] [Google Scholar]
- Rommens J. M., Iannuzzi M. C., Kerem B., Drumm M. L., Melmer G., Dean M., Rozmahel R., Cole J. L., Kennedy D., Hidaka N. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 1989 Sep 8;245(4922):1059–1065. doi: 10.1126/science.2772657. [DOI] [PubMed] [Google Scholar]
- Teng H., Jorissen M., Van Poppel H., Legius E., Cassiman J. J., Cuppens H. Increased proportion of exon 9 alternatively spliced CFTR transcripts in vas deferens compared with nasal epithelial cells. Hum Mol Genet. 1997 Jan;6(1):85–90. doi: 10.1093/hmg/6.1.85. [DOI] [PubMed] [Google Scholar]